The present invention relates to substituted 3,3-diamino-2-propenenitriles, in the following also referred to as cyanoenamines, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy e.g. in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinologic system.
Optionally, the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, e.g. an antidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism. Suitable antidiabetics comprise insulin as well as orally active hypoglycemic agents such as sulphonylureas, e.g. glibenclamide and glipizide; biguanides, e.g. metformin; benzoic acid derivatives, e.g. repaglinide; and thiazolidinediones, e.g. troglitazone and ciglitazone.
Potassium channels play an important role in membrane potential. Among the different types of potassium channels are the ATP-sensitive (KATP-) channels which are regulated by changes in the intracellular concentration of adenosine triphosphate. The KATP-channels have been found in cells from various tissues such as cardiac cells, pancreatic-cells, skeletal muscles, smooth muscles, central neurones and adenohypophysis cells. The channels have been associated with diverse cellular functions for example hormone secretion (insulin from pancreatic beta-cells, growth hormone and prolactin from adenohypophysis cells), vasodilation (in smooth muscle cells), cardiac action potential duration, neurotransmitter release in the central nervous system.
Modulators of the KATP-channels have been found to be of importance for the treatment of various diseases. Certain sulfonylureas which have been used for the treatment of non-insulin-dependent diabetes mellitus act by stimulating insulin release through an inhibition of the KATP-channels on pancreatic beta-cells. The potassium channel openers, which comprise a heterogeneous group of compounds, have been found to be able to relax vascular smooth muscles and have therefore been used for the treatment of hypertension.
In addition, potassium channel openers can be used as bronchodilators in the treatment of asthma and various other diseases.
Furthermore, potassium channel openers have been shown to promote hair growth, and have been used for the treatment of baldness.
Potassium channel openers are also able to relax urinary bladder smooth muscle and therefore, can be used for the treatment of urinary incontinence. Potassium channel openers which relax smooth muscle of the uterus can be used for treatment of premature labor.
Since some KATP-openers are able to antagonize vasospasms in basilar or cerebral arteries the compounds of the present invention can be used for the treatment of vasospastic disorders such as subarachnoid hemorrhage and migraine.
Potassium channel openers hyperpolarizes neurons and inhibit neurotransmitter release and it is expected that the present compounds can be used for the treatment of various diseases of the central nervous system, e.g. epilepsia, ischemia and neurodegenerative diseases, and for the management of pain.
Recently, it has been shown that diazoxide (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide) and certain 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide derivatives inhibit insulin release by an activation of KATP-channels on pancreatic beta-cells (Pirotte B. et al. Biochem. Pharmacol, 47, 1381-1386 (1994); Pirotte B. et al., J. Med. Chem., 36, 3211-3213 (1993). Diazoxide has furthermore been shown to delay the onset of diabetes in BB-rats (Vlahos W D et al. Metabolism 40, 39-46 (1991)). In obese zucker rats diazoxide has been shown to decrease insulin secretion and increase insulin receptor binding and consequently improve glucose tolerance and decrease weight gain (Alemzadeh R. et al. Endocrinol. 133, 705-712, 1993). It is expected that such potassium channel openers can be used for treatment of diseases characterized by an overproduction of insulin and for the treatment and prevention of diabetes.
The present invention relates to substituted 3,3-diamino-2-propenenitriles, in the following also referred to as cyanoenamines, of the general formula I: 
wherein
R1 is alkyl optionally substituted with halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; or aralkyl optionally substituted with alkyl, trifluoromethyl, aryl, a 5-,6- or 7-membered heterocyclic system, halogen, alkoxy, methylenedioxo, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or aryl optionally substituted with alkyl, trifluoromethyl, aryl, a 5-,6- or 7-membered heterocyclic system, halogen, alkoxy, methylenedioxo, aryloxy, dialkylamino, alkylarylamino, diaryl-amino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or a 5-,6- or 7-membered heterocyclic system optionally substituted with alkyl, aryl, a 5-,6- or 7-membered heterocyclic system, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl;
R2 and R3 are independently hydrogen, alkyl optionally substituted with aryl, a 5-,6- or 7-membered heterocyclic system, halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aryl, optionally substituted with alkyl, aryl, a 5-,6- or 7-membered heterocyclic system, halogen, trifluoromethyl, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; a 5-,6- or 7-membered heterocyclic system optionally substituted with alkyl, aryl, a 5-,6- or 7-membered heterocyclic system, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl;
or R2 and R3 are linked together by xe2x80x94(CH2)nxe2x80x94, n being 4-7, provided that R2 and R3 cannot be hydrogen at the same time;
Z is hydrogen, cyano, carbonylalkyl, alkoxycarbonyl, optionally substituted aminocarbonyl, alkylsulfonyl or arylsulfonyl optionally substituted with alkyl, aryl, a 5-,6- or 7-membered heterocyclic system, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or arylsulfonyl optionally substituted with alkyl, aryl, a 5-,6- or 7-membered heterocyclic system, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl;
or pharmaceutically acceptable salts thereof.
Within its scope the invention includes all diastereomers and enantiomers of compounds of formula I, some of which are optically active, and also their mixtures including racemic mixture thereof.
The scope of the invention also includes all tautomeric forms of the compounds of formula I as well as metabolites or prodrugs.
In a preferred embodiment of the invention, Z is alkylsulfonyl or arylsulfonyl substituted with halogen. More preferred, Z is methylsulfonyl, isopropylsulfonyl or 4-chlorophenylsulfonyl.
In a further preferred embodiment of the invention, R1 is optionally substituted aryl. More preferred optionally substituted phenyl and most preferred phenyl substituted by one or two perhalomethyl groups, one or two alkoxy groups, one or two halogen groups or one or two cyano groups.
A preferred perhalomethyl group is trifluoromethyl.
The most preferred phenyl substituents are 3,5-dichloro or 3,5-dialkoxy substituents.
In a further preferred embodiment of the invention, R2 is cyclic alkyl with from 3 to 5 carbon atoms in the ring, most preferred is cyclobutyl.
In another preferred embodiment of the invention, R2 is 1,1-dimethylpropyl.
A xe2x80x9cmetabolitexe2x80x9d of a compound disclosed in this application is an active derivative of a compound disclosed herein which is produced when the compound is metabolized. Metabolites of compounds disclosed herein can be identified either by administration of a compound to a host and an analysis of blood samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the incubant. A xe2x80x9cprodrugxe2x80x9d is a compound that either is converted into a compound disclosed in the application in vivo or has the same active metabolite as a compound disclosed in this application.
The salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methane-sulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like.
The term xe2x80x9c5-,6- or 7-membered heterocyclic systemxe2x80x9d as used herein refers to: a monocyclic unsaturated or saturated system containing one, two or three hetero atoms selected from nitrogen, oxygen and sulfur and having 5 members, e.g. pyrrole, furan, thiophene, pyrroline, dihydrofuran, dihydrothiophene, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, thiazole, isoxazole, isothiazole, 1,2,3-oxadiazole, furazan, 1,2,3-triazole, 1,2,3-thiadiazole or 2,1,3-thiadiazole; an aromatic monocyclic system containing two or more nitrogen atoms and having 6 members, e.g. pyrazine, pyrimidine, pyridazine, 1,2,4-triazine, 1,2,3-triazine or tetrazine; a non-aromatic monocyclic system containing one or more hetero atoms selected from nitrogen, oxygen and sulfur and having 6 or 7 members, e.g. pyran, thiopyran, piperidine, dioxane, oxazine, isoxazine, dithiane, oxathine, thiazine, piperazine, thiadiazine, dithiazine, oxadiazine or oxoazepane.
Alkyl refers to lower straight, cyclic, bicyclic, fused or branched alkyl having 1 to 15 carbon atoms, preferentially 1 to 6 carbon atoms. Aryl refers to phenyl or phenyl substituted with alkyl or phenyl, or phenyl fused with cycloalkyl, or polycyclic aromatic systems such as naphthyl, anthracenyl, phenanthrenyl, fluorenyl, etc. Alkylene refers to lower straight, cyclic, fused or branched alkylene having 1 to 15 carbon atoms, preferentially 1 to 6 carbon atoms. Alkoxy refers to xe2x80x94O-alkyl and aryloxy refers to xe2x80x94O-aryl. Cyano refers to xe2x80x94CN, hydroxy refers to xe2x80x94OH, amino refers to xe2x80x94NH2 and nitro refers to xe2x80x94NO2. Dialkylamino refers to xe2x80x94N(alkyl)2. Alkylarylamino refers to xe2x80x94N(alkyl)(aryl) and diarylamino refers to xe2x80x94N(aryl)2. Halogen refers to xe2x80x94F, xe2x80x94Cl, xe2x80x94Br and xe2x80x94I. Aralkyl refers to -alkylene-aryl. Alkylthio refers to xe2x80x94S-alkyl and arylthio refers to xe2x80x94S-aryl. Alkoxycarbonyl refers to xe2x80x94COxe2x80x94O-alkyl and aminocarbonyl refers to xe2x80x94COxe2x80x94N(alkyl)2, xe2x80x94COxe2x80x94N(alkyl)(aryl) or xe2x80x94COxe2x80x94N(aryl)2. Carbonylalkyl refers to xe2x80x94CO-alkyl. A leaving group refers to a group or atom capable of existing in solution as a negatively charged species, or a positively charged group or atom.
The compounds of the present invention interact with the potassium channels and hence act as openers or blockers of the ATP-regulated potassium channels, which make them useful in the treatment of various diseases of the cardiovascular system, e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases; the pulmonary system; the gastrointestinal system; the central nervous system and the endocrinologic system.
The compounds of the present invention may also be used for the treatment of diseases associated with decreased skeletal muscle blood flow such as Reynauds disease and intermittent claudication.
Further, the compounds of the invention may be used for the treatment of chronic airway diseases, including asthma, and for treatment of detrusor muscle instability secondary to bladder outflow obstruction and therefore for kidney stones by aiding their passage along the ureter. Potassium channel openers also relax urinary bladder smooth muscle, thus, the compounds of the present invention can be used for the treatment of urinary incontinence.
The present compounds could also be used for treatment of conditions associated with disturbances in gastrointestinal mobility such as irritable bowel syndrome. Additionally these compounds can be used for the treatment of premature labor and dysmenorrhea.
Further, potassium channel openers promote hairgrowth, therefore, the compounds of the present invention can be used for the treatment of baldness.
In diseases such as nesidioblastosis and insulinoma in which a hypersecretion of insulin causes severe hypoglycemia the compounds of the present invention can be used to reduce insulin secretion. In obesity hyperinsulinemia and insulin resistance is very frequently encountered. This condition could lead to the development of noninsulin dependent diabetes (NIDDM). It is expected that potassium channel openers and hence the compounds of the present invention can be used for counteracting the hyperinsulinemia and thereby prevent diabetes and reduce obesity. In overt NIDDM treatment of hyperinsulinemia with potassium channel openers, and hence the present compounds, can be of benefit in restoring glucose sensitivity and normal insulin secretions.
In early cases of insulin dependent diabetes (IDDM) or in prediabetic cases, potassium channel openers and hence the present compounds can be used to induce betacell rest which may prevent the progression of the autoimmune disease.
Compounds of the present invention which act as blockers of KATP-channels can be used for the treatment of NIDDM.
Preferably, the compounds of the present invention may be used for treatment or prevention of diseases of the endocrinologic system such as hyperinsulinemia and diabetes.
Accordingly, in another aspect the invention relates to a compound of the general formula I or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hyperinsulinemia and treatment or prevention of diabetes.
Furthermore, the invention also relates to the use of the inventive compounds of formula I as medicaments useful for treating hyperinsulinemia and treating or preventing diabetes.
In yet another aspect, the present invention relates to a method of preparing compounds of the invention.
The method comprises synthesis of cyanoenamines by the following reaction scheme: 
Acceptor substituted acetonitriles were reacted with isothiocyanates in the presence of a base. The resulting salts of the adducts were treated with alkyl halide to give the corresponding alkylsulfanyl propenenitriles, which were reacted with primary and secondary amines to give cyanoenamines of formula I.
Some derivatives of 2-cyano-3-(dimethylamino)-3-arylamino-2-propenenitriles have been claimed to be angiotensin II antagonists (EP 591891, Chem. Abstr. 1995, 122, 81364; Chem. Abstr. 1994, 121, 300890). Example: 
Other compounds containing this substructural element have been claimed to be antithrombotics (EP 547517, Chem. Abstr. 1993, 119, 249845; Chem. Abstr. 1993, 119, 180666), e.g.: 
Several 3-(arylamino)-3-(alkylamino)-2-cyano-2-propenenitriles and -2-acrylamides have been claimed as fungicides and herbicides (EP 10396, Chem. Abstr. 1982, 97, 140276; Chem. Abstr. 1980, 93, 144701), some examples being: 
The reaction of amines RRxe2x80x2NH with mono-imidates of malononitrile of the general formula NCxe2x80x94CH2xe2x80x94C(OR)xe2x95x90NH give compounds of the type RRxe2x80x2Nxe2x80x94C(NH2)xe2x95x90CHxe2x80x94CN, where one of the two amino groups is limited to be NH2 (Cocco, M. T.; Congiu, C.; Maccioni, A.; Plumitallo, A., J. Heterocycl. Chem., 1989, 26,1859-1862; Klemm, K.; Pruesse, W.; Baron, L.; Daltrozzo, E., Chem. Ber., 1981, 114, 2001-2018; Cocco, M. T.; Onnis, V., Synthesis, 1993, 2, 199-201; Fanshawe, W. J. et al., J. Org. Chem., 1964, 29, 308-311; Troschuetz, R.; Dennstedt, T., Arch. Pharm. (Weinheim Ger.), 1994, 327, 85-90).
A further method consists in the reaction of O-alkylated cyanoacetamides with aliphatic amines (G. J. Durant et al., patent, CH 606026, Chem. Abstr. 1979, 90, 87449, G. J. Durant, U.S. Pat. No. 4,024,260, Chem. Abstr., 1977, 87, 135327). Also the reaction of 3,3-dimethoxyacrylonitrile with amines, which can be carried out stepwise in order to prepare compounds of the general formula RRxe2x80x2Nxe2x80x94C(NRxe2x80x3Rxe2x80x2xe2x80x3)xe2x95x90CHxe2x80x94CN, has been reported (G. J. Durant, U.S. Pat. No. 4,277,485, Chem. Abstr., 1981, 95, 156591) and used for the preparation of ranitidine-analogues.
Moreover, the reaction of 3,3-dichloroacrylonitrile with amines has been reported to give cyanoenamines of the general structure (RRxe2x80x2N)2Cxe2x95x90CHxe2x80x94CN, with two identical amine-moieties RRxe2x80x2Nxe2x80x94 (Hashimoto et al., J. Org. Chem., 1970, 35, 828-831; Takeda Chem.Ind.Ltd., JP 7022328, 1970, Chem.Abstr., 73, 98434z). In addition to these, some special methods for the synthesis of these compounds have been described (e.g. Sasaki, T.; Kojima, A. J. Chem. Soc. Sec. C, 1970, 476-480; Clark, J., Parvizi, B., Southon, I. W., J. Chem. Soc., Perkin Trans. 1, 1976, 125-130; Smith; Kline and French Lab. Lim, FR 2229417, DE 2423813, Chem. Abstr., 82, 170943; Meyer; K., Justus Liebigs Ann. Chem., 1978, 1491; Elagamey, A. G. A.; El-Taweel, F. M. A., J. Prakt. Chem., 1991, 333, 333-338).
For the preparation of 2-acceptor-substituted 3,3-bis(alkyl/arylamino)-2-propenenitriles, several different synthetic methods have been described (Elvidge, J. A. et al., J. Chem. Soc., Perkin Trans. I, 1983, 1741-1744; Yatsishin, A. A.. et al., Zh. Org. Khim. 1979, 15, 1381-1384; Hartke, K., Angew. Chem. 1964, 76, 781)
Pharmacological Methods
The ability of the compounds to interact with potassium channels can be determined by various methods. When patch-clamp techniques (Hamill O. P., Marty A., Nefer E., Sakman B. and Sigworth F. J., Plxc3xcgers Arch. 1981, 391, 85-100) are used the ionic current through a single channel of a cell can be recorded.
The activity of the compounds as potassium channel openers can also be measured as relaxation of rat aortas rings according to the following procedure:
A section of rat thoracic aorta between the aortic arch and the diaphragm was dissected out and mounted as ring preparations as described by Taylor P. D. et al. , Brit. J. Pharmacol., 1994, 111, 42-48.
After a 45 min. equilibration period under a tension of 2 g, the preparations were contracted to achieve 80% of the maximum response using the required concentration of phenylephrine. When the phenylephrine response reached a plateau, potential vasodilatory agents were added cumulatively to the bath in small volumes using half log molar increments at 2 min intervals. Relaxation was expressed at the percentage of the contracted tension. The potency of a compound was expressed as the concentration required to evoke a 50% relaxation of the tissue.
In the pancreatic beta-cell the opening of the KATP-channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Ca2+ concentration according to the method of Arkhammer P. et al. , J. Biol. Chem. 1987, 262, 5448-5454.
86Rb+ Efflux from a xcex2-cell Line
The RIN 5F cell line was grown in RPMI 1640 with Glutamax I, supplemented with 10% fetal calf serum (from GibcoBRL, Scotland, UK) and maintained in an atmosphere of 5% CO2/95% air at 37xc2x0 C. The cells were detached with a Trypsin-EDTA solution (from GibcoBRL, Scotland, UK), resuspended in medium, added 1 mCi/mL 86Rb+ and replated into microtiter plates (96 well cluster 3596, sterile, from Costar Corporation, MA, USA) at a density of 50000 cells/well in 100 xcexcl/well, and grown 24 hours before use in assay.
The plates were washed 4 times with Ringer buffer (150 mM NaCl, 10 mM Hepes, 3.0 mM KCl, 1.0 mM CaCl2, 20 mM sucrose, pH 7.1). Eighty xcexcL Ringer buffer and 1 xcexcL control- or test compound dissolved in DMSO was added. After incubation 1 h at room temperature with a lid, 50 xcexcL of the supernatant was transferred to PicoPlates (Packard Instrument Company, CT, USA) and 100 xcexcL MicroScint40 (Packard Instrument Company, CT, USA) added. The plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1 min/well at the 32P program.
The calculation of EC50 and Emax was done by SlideWrite (Advanced Graphics Software, Inc., CA, USA) using a four parameter logistic curve: y=(axe2x88x92d)/(1+(x/c)b)+d, where a=the activity estimated at concentration zero, b=a slope factor, c=the concentration at the middle of the curve and, d=the activity estimated at infinite concentration. EC50=c and EMmax=d, when the curve is turned of at infinite concentrations.
In addition the effect of KATP-channel modulators on pancreatic beta-cells can be determined by measuring the increase or decrease in insulin release from insulin producing beta-cell lines or isolated islets.
Effect of KATP-channel modulators can be measured using the following procedure: The beta cells are cultured with change of media every three-four days.
Cells are then seeded in 96 well microtiter dishes and cultured for three day at 38xc2x0 C., 5% CO2 and 95% humidity.
The cells are washed with NN -buffer (+10 mM Hepes+0.1% BSA) for one minute and glucose (final conc. 22 mM), IBMX (final conc.0.1 mM) and compounds (final conc. from 5xc3x9710xe2x88x925 M-5xc3x9710xe2x88x928 M) added. All cells are then incubated for three hours (38xc2x0 C., 5% CO2 and 95% humidity).
Supernates are harvested into Greiner minisorb microtiter wells and frozen. Insulin is measured using elisa-techniques.
The compounds of the present invention shows high selectivity of the insulin release test compared to the relaxation of rat aorta rings test.
The compounds according to the invention are effective over a wide dosage range. In general satisfactory results are obtained with dosages from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, per day. A most preferable dosage is about 5 mg to about 200 mg per day. The exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet, appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
Due to their high degree of activity, the compounds of the invention may be administered to a mammal, especially a human, in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above and especially of diseases of the endocrinologic system such as hyperinsulinemia and diabetes. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.